Discovery and optimization of pyrazolopyrimidine sulfamates as ATG7 inhibitors.

吡唑并嘧啶氨基磺酸盐作为 ATG7 抑制剂的发现和优化。

• 影响指数: 3.461
• 发表时间: 10 2020 1
• 来源期刊: Bioorg Med Chem
• DOI: 10.1016/j.bmc.2020.115681
• PMID: 32912429
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 医学
• 作者列表: Huang SC,Adhikari S,Brownell JE,Calderwood EF,Chouitar J,D'Amore NR,England DB,Foley K,Harrison SJ,LeRoy PJ,Lok D,Lublinsky A,Ma LT,Menon S,Yang Y,Zhang J,Gould AE

关键词: ATG7; ATG7 inhibitor; Autophagy; E1 enzyme

Mesh: Autophagy / drug effects; Autophagy-Related Protein 7 / antagonists & inhibitors metabolism; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Molecular Structure; Pyrazoles / chemical synthesis chemistry pharmacology; Pyrimidines / chemical synthesis chemistry pharmacology; Structure-Activity Relationship; Sulfonic Acids / chemical synthesis chemistry pharmacology

Abstract

Autophagy is postulated to be required by cancer cells to survive periods of metabolic and/or hypoxic stress. ATG7 is the E1 enzyme that is required for activation of Ubl conjugation pathways involved in autophagosome formation. This article describes the design and optimization of pyrazolopyrimidine sulfamate compounds as potent and selective inhibitors of ATG7. Cellular levels of the autophagy markers, LC3B and NBR1, are regulated following treatment with these compounds.

摘要

假定自噬是癌细胞在代谢和/或低氧应激时期存活所必需的。ATG7是激活参与自噬体形成的Ubl缀合途径所需的E1酶。本文介绍了吡唑并嘧啶氨基磺酸盐化合物作为ATG7的有效和选择性抑制剂的设计和优化。细胞水平的自噬标志物，LC3B和NBR1在用这些化合物处理后受到调节。